1. Field of the Invention
The invention relates to sterilizable biopharmaceutical packages, and its object is more particularly a biopharmaceutical packaging that can be sterilized on the inside, a process for implementing such a packaging, and, finally, a unit that comprises a biopharmaceutical packaging and its sterilized biopharmaceutical contents.
2. Description of the Related Art
Here, biopharmaceutical is defined as that which relates to biotechnology or pharmacy.
It is known that, in the biopharmaceutical field, it is necessary to package biopharmaceutical contents that are brought in the sterile state in disposable, flexible packages for purposes of storage, shipping, handling, and transfer, for example into or from sterile chambers.
Biopharmaceutical contents such as those concerned here are in the solid state and capable of being handled and transferred. They may involve, for example, a sterile object such as a container, a container element such as a stopper, a syringe, but also elements for environmental control that are used within the framework of the biopharmaceutical process.
A first type of biopharmaceutical packaging that can be sterilized on the inside, capable of enclosing such biopharmaceutical contents to be sterilized comprising a flexible outer wall consisting of a part that is sealed against gases and pathogenic germs and a part that is permeable to a sterilization gas in the direction from the outside to the inside (namely, the direction extending from the outside to the inside of the packaging), is already known. Before sterilization, the sterilizable packaging comprises an opening for introduction of the biopharmaceutical contents to be sterilized from the outside to the inside of the packaging, with this introduction opening then being in the open state. This introduction opening is capable of being closed in an airtight manner once the biopharmaceutical contents are brought into the inside receiving space of the packaging. It is provided that after sterilization and at the time when this is desired, the sterilized packaging comprises an opening for extracting the sterilized biopharmaceutical contents, with this extraction opening then being in the open state, in such a way as to release the biopharmaceutical contents from the packaging for the purpose of the desired use. Previously, this extraction opening was closed in an airtight manner or was non-existent. It is also provided that the part of the outer wall that is permeable to sterilization gases is capable of being associated with, i.e., brought into communication with, a suitable source of sterilization gas, for example the sterilization gas of a sterilization chamber, in such a way that the sterilization gas that comes from the source in question is able to penetrate into the packaging by this permeable part. For implementing such a packaging, the biopharmaceutical contents that are to be sterilized are put into the inside receiving space of the packaging designed to enclose it, via the introduction opening previously opened and subsequently sealed in an airtight manner. Then, the sterilization gas is injected into the inside receiving space where the biopharmaceutical contents are located, via the part that is permeable to sterilization gas, which thus ensures the desired sterilization. At the time desired after sterilization, the opening for extracting the sterilized biopharmaceutical contents is opened in such a way as to extract said contents from the packaging so as to use them as desired.
In a nonlimiting manner, sterilization is defined here as the processes for sterilization by saturated water vapor, by dry heat, or else by toxic gases such as ethylene oxide (ETO), vapor-formaldehyde or else hydrogen peroxide (H2O2). During the sterilization of the biopharmaceutical contents, the environment surrounding the biopharmaceutical contents to be sterilized and the inside receiving space of the packaging that encloses the biopharmaceutical contents to be sterilized are filled with suitable sterilization gas, in such a way as to destroy, to a certain desired measure or in the required measurement, the pathogenic germs.
Sealed closing is defined as a closing sealed against gases, including water vapor, and pathogenic germs.
A part that is permeable to sterilization gas is defined as the capability of a separation element such as a wall, including a flexible wall such as a membrane, to allow the passage, at least in one direction, of a suitable sterilization gas, including in the form of vapor, such as water vapor.
In a first embodiment, the sterilization is carried out on the site of use of the biopharmaceutical contents, these thus packaged and sterilized contents then being ready for use and having to be used shortly after sterilization, in hopes that the integrity of the packaging has been preserved. Actually, with such an embodiment in which the permeable part remains permeable and in contact with the ambient atmosphere, even after sterilization, it is not possible to implement a process for monitoring the integrity of the packaging because of the presence of this permeable part. However, with such an embodiment, monitoring of integrity would be all the more necessary as the risk of deterioration of the permeable part after sterilization becomes high, in particular in the case of shipping or handling.
In a second embodiment, monitoring of integrity is done by placing the packaging that encloses the sterilized biopharmaceutical contents in an outer packaging pouch, with a differential pressure being created between the very interior of the packaging and the inside part of the outer packaging pouch that is outside of the packaging. This second embodiment has the drawback of requiring complicated handling and a significant amount of operating time to be able to detect a differential pressure change that signifies a loss of integrity.
It is known that in the biopharmaceutical field, it is essential to ensure that the flexible pouches are airtight, or at least have a degree of sealing that is deemed satisfactory. There are several integrity monitoring processes of such pouches.
The standard F 2095-01 of ASTM International whose title is “Standard Test Methods for Pressure Decay Leak Test for Nonporous Flexible Packages With and Without Restraining Plates” relates more specifically to the so-called pressure drop process. This process is envisaged according to two possible embodiments: with expansion limitation plates or without such plates. The document WO 2009/095572 relates to an integrity monitoring process in the case of a pouch with side gussets.
It is also known that in the biopharmaceutical field, it is common to use either pouches whose two large walls are directly joined to one another in such a way that once expanded, they have a limited volume and remain relatively thin, or pouches with gussets such that once expanded, they have a volume that can be much larger.
Consequently, with the first type of sterilizable biopharmaceutical packaging described above, the problem of the monitoring of integrity of the packaging is encountered, with the induced consequences: necessity of implementing sterilization on the site of use of the biopharmaceutical contents, necessity of quickly using the packaged and sterilized contents, or else implementation of a long and complex integrity monitoring.
A second type of packaging that corresponds to a closer state of the art is described in the document U.S. Pat. No. 7,040,485. Here, the packaging comprises a flexible outer wall, sealed against gases and pathogenic germs; an opening for introduction of the packaging of the biopharmaceutical contents to be sterilized from the outside to the inside, subsequently capable of being closed in an airtight manner; an inside space capable of receiving the biopharmaceutical contents; a sterilization gas conveyance channel from the outside of the packaging, comprising at least one upstream opening for intake of sterilization gas, toward the outside of the packaging, able to be associated in communication with a sterilization gas source, at least one downstream opening for distribution of sterilization gas that empties into the inside space, and a communication between the at least one upstream intake opening and the at least one downstream distribution opening; and, finally, means for control of the distribution of sterilization gas into the inside space.
In this second type of packaging, the outer wall is a sheath that comprises a first segment and a second segment that are adjacent to the location of a side that is open before sterilization and closed during sterilization. On one of its two surfaces, the first sheath segment comprises a part that is permeable to sterilization gas belonging to a sterilization gas conveyance channel from the outside of the packaging. The first sheath segment also comprises an end opening for introduction into the packaging of the biopharmaceutical contents to be sterilized, then in the open state. This introduction opening is located opposite the open side. The second sheath segment is closed on its periphery, except for the open side before sterilization, and closed during sterilization. The second sheath segment forms an inside space for receiving biopharmaceutical contents to be sterilized. The packaging also comprises means for control of the distribution of sterilization gas in the inside space so that it accesses or it can access the environment enveloping the contents to be sterilized and the inside space of the packaging that encloses it. For the implementation of such a packaging, the biopharmaceutical contents to be sterilized are introduced into the packaging by passage through the end introduction opening, and then by crossing the first segment, namely passage in front of the segment that is permeable to sterilization gas and passage through the open side. Thus, the biopharmaceutical contents access the inside receiving space in which it is placed for sterilization. The end introduction opening is then sealed on itself and thus closed, while the side is kept open. The sterilization gas is then introduced into the packaging, from the outside of the packaging, through the permeable part. Thus, the sterilization gas penetrates into the first sheath segment and then, passing through the open side, penetrates into the second sheath segment. The sterilization of the biopharmaceutical contents is thus ensured. The open side is then sealed on itself and thus closed. The packaging is then split into two, with the two sheath segments being separated, the sheath being cut crosswise toward the open side that was previously sealed.
Thus, with this second type of packaging, the open side serves both in the introduction of the biopharmaceutical contents to be sterilized and in the sterilization gas conveyance channel. Consequently, the open side that is adjacent to the inside space cannot be closed independently and before the closing of the sterilization gas conveyance channel.
In contrast, the opening for introduction of the biopharmaceutical contents to be sterilized is separated from the inside space for receiving the biopharmaceutical contents to be sterilized and the sterilized biopharmaceutical contents, in such a way that the biopharmaceutical contents to be sterilized are introduced into the inside space from the outside of the packaging only in an indirect manner. Such an embodiment is therefore problematic to implement in some cases, taking into account the shape or the size of the packaging or the nature, the shape and the size of the biopharmaceutical contents.
The same drawback is encountered with the packages described in the documents WO 2004/039419 and FR-A-2820118.
Also, the control means for the distribution of sterilization gas are opening/closing means of the side that participates in the introduction of contents to be sterilized in the packaging, in such a way that the sterilization gas conveyance channel cannot be opened or closed independently of the opening or closing of the introduction of the contents to be sterilized.
Finally, once the sterilization is done, the outer wall, the sterilization gas conveyance channel and the opening/closing means are necessarily separated into two. Taking into account that in the sterilized packaging, there is no longer a permeable part, the latter having been removed, it is possible to implement a process for monitoring the integrity of the packaging whose wall is made airtight in manufacturing and which is expected to remain airtight. However, this possibility of implementing an integrity monitoring process is achieved only at the expense of cutting the packaging for separating the two sheath segments. However, such an operation for cutting the sheath is always difficult because, specifically, it may compromise the integrity of the packaging.
Consequently, with the second type of sterilizable biopharmaceutical packaging described above, the problem of the difficulty of passing the biopharmaceutical contents into the inside space and the problem of the risk of deterioration of the integrity of the packaging as a result of its being cut are encountered.
The document U.S. Pat. No. 4,583,643 that describes a flexible packaging designed to receive items that can be automatically sterilized in such a way as to ensure their integrity is also known from the state of the art. The flexible packaging has a first module that forms a valve and an actuator positioned on the upper wall and a second module that forms a valve and an actuator positioned on the lower wall. Each of these modules that forms a valve and an actuator is equipped with a support part that comprises a large number of holes acting as openings so as to allow the passage of a fluid flow inside and outside of the flexible packaging and a valve that is used to reclose the holes.
The document U.S. Pat. No. 4,296,862 that describes a part that is designed to constitute a sterile barrier so as to keep the interior of a packaging device under sterile conditions is known.
The document WO 03/068274 that relates to a system that makes it possible to inject ozonized gas inside a packaging that contains an object to be disinfected or sterilized is also known. The packaging comprises coupling means that make it possible for it to be combined with said injection system to ensure the introduction of ozonized gas into the chamber that receives the object to be sterilized, as well as closing means that make it possible to ensure the sealing of the chamber when the packaging is no longer associated with the system.
Furthermore, the document EP 1 520 795 that describes a packaging for pharmaceutical products that is formed from a first impermeable foil, a second impermeable foil welded to the first, and a permeable clasp welded to the second foil and able to be welded to the first foil is known. These three foils form an inside space into which an object can be introduced for the purpose of its sterilization. When said sterilization operation is terminated, the portion of the packaging containing the permeable clasp is cut into sections, and the first and second impermeable foils are welded to one another in such a way as to constitute an inside space delimited only by these first and second impermeable foils. As above, such a cutting operation is dangerous because it can compromise the integrity of the packaging.